Despite political pressure favoring tighter drug regulations, the FDA has prepared a plan that may hasten the testing and approval of investigational molecular imaging agents.
A draft guidance for the proposed exploratory investigational new drug (eIND) application was published in April and posted in the Federal Register for comment.
The eIND guidance appears to accept the molecular imaging community's position that MI nuclear probes are extremely safe. It proposes a faster way for researchers to move from preclinical trials involving animal testing to phase I safety and biodistribution testing in human subjects. Less pharmaceutical and toxicological evaluation would be required before initiation of human trials, according to Dr. George Mills, director of the FDA's division of medical imaging and radiopharmaceutical drug products.
"The measures in the eIND would put the drug developers in a position where they can reduce costs and speed the research and development process," Mills said.
Nuclear medicine researchers have contended for years that toxicology and pharmacology studies for radioactive drugs should follow a different set of rules from those established for traditional drugs, said Dr. Robert Innis, chief of the molecular imaging branch of the National Institutes of Health. MI agents are typically given only once and at very low doses that have no pharmacological or toxicological effect.
"It makes sense to have reduced barriers for entry in humans in comparison to therapeutic agents that are given many times and in bigger doses," he said.
Dr. Dennis Swanson, chair of the Radioactive Drug Research Committee at the University of Pittsburgh, expects that the exploratory IND draft will address the need for a different approach for radioactive tracers, and he is optimistic that this could open up a world of radioactive drugs for clinical use.
"The exploratory IND is getting at our issues and should allow for first-in-humans testing at low dosage levels," he said.
Because adverse reactions are unlikely, PET molecular imaging probes warrant a blanket classification indicating that they pose no significant risk, said Dr. Jorge Barrio, a professor of molecular and medical pharmacology at the University of California, Los Angeles. If cumbersome barriers were eliminated, the cost of implementing a new PET probe could be cut by $250,000, he said.
Costs could also be reduced by eliminating unnecessary redundancy, according to Dr. Robert Mach, a professor of radiology at the Mallinckrodt Institute of Radiology.
The current safety profile protocol requires extensive tests on animals that are then repeated with human subjects. The FDA defines a safe drug as one that may be administered without adverse reaction in multiple doses 10 to 1000 times larger than the doses that would realistically be used in clinical practice.
The high cost of proving that an imaging agent is safe enough for human use has often discouraged researchers from pursuing approvals, Mach said. He learned that lesson while working with F-18 FCP-PET at Wake Forest University. His colleagues decided against moving the promising neurological radiopharmaceutical into clinical trials despite a clean safety record after nearly 1000 studies on macaque monkeys.
Considering how the FDA handled the review of fluorine-18 fluorodeoxyglucose (FDG) in the 1990s, some MI researchers doubt that a less rigorous track for new PET radiopharmaceutical agents will be adopted. Dr. Carol Marcus, a professor radiation oncology and radiological sciences at UCLA, recalled the numerous delays that arose during the FDA's 20-year-long review of FDG. The agent has since established one of the best safety records for a diagnostic pharmacological agent.
"How many adverse reactions have there been to FDG? None. Not one in the U.S. Not one in the world," Marcus said.
Congress addressed numerous problems with the FDA's regulation of investigational PET agents in the FDA Modernization Act of 1997. MI researchers see the eIND as a way for the agency to independently solve residual problems, but they worry that the controversy concerning the regulation of Vioxx and other COX-2 inhibitors could jeopardize plans to streamline the regulatory process. Deaths associated with molecularly based therapeutic agents that went through the FDA's accelerated approval process have led public health advocates and some members of Congress to demand tighter regulations.
But an FDA report published in February suggests that the regulatory experience with Vioxx should have the opposite effect. The report concludes that traditional animal testing did not help predict cardiovascular problems that led to deaths attributed to Vioxx, and it mentions the possible use of microdose testing in humans with PET agents as an alternative, Mach said.
"The current requirements are no more valuable in predicting how imaging agents will work in humans than the similar studies for Vioxx were in predicting the toxicological effects of that drug," he said.
Although the draft guidance sounds promising to MI researchers, the terms of actual reform resulting from the document could change substantially after the subsequent public comment and review, according to the FDA's Mills. The timing of implementation is uncertain.
Comments regarding the draft document can be submitted up to 90 days after its publication. It can be examined at www.fda.gov/cder/guidance/6384dft.htm#_Toc10063807.